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Objective: To explore the synergistic effect of nano-pearl powder (NPP) and adipose-derived stem cell exosomes (ADSC-Exos) on the osteogenic potential of MC3T3-E1 cells.

Methods: The water-soluble matrix of NPP (NPP-WSM) was extracted via freeze-drying, and ADSC-Exos were isolated by ultracentrifugation. NPP-WSM was incorporated into ADSC-Exos through co-incubation to generate NPP-WSM-Exos. MC3T3-E1 cells were treated with NPP-WSM or NPP-WSM-Exos. Cell proliferation and migration were evaluated using CCK-8 and wound-healing assays, respectively. Osteogenic differentiation was assessed by Alizarin Red S staining and alkaline phosphatase (ALP) activity. The expression of osteogenesis-related genes (COL1A1, RUNX2, OCN, and OPN) was measured by qPCR and Western blotting. Transcriptome sequencing (RNA-seq) was conducted to identify signaling pathways activated by NPP-WSM-Exos.

Results: NPP-WSM-Exos displayed distinct exosome morphology and biomarkers, confirming their successful preparation. Significantly, NPP-WSM-Exos enhanced the viability of MC3T3-E1 cells compared to NPP-WSM alone and upregulated the expression of osteogenic genes, including COL1A1, RUNX2, OCN, and OPN, at both the transcriptional and translational levels. Additionally, NPP-WSM-Exos strongly promoted mineralization, as evidenced by the increased calcification observed through Alizarin Red S staining, and elevated alkaline phosphatase (ALP) activity, indicating excellent potential for osteogenic differentiation. Transcriptome sequencing showed that NPP-WSM-Exos significantly enhanced the PI3K/AKT pathway in MC3T3-E1 cells, while protein level detection indicated that NPP-WSM-Exos could increase AKT phosphorylation levels and inhibit GSK3β activity to improve osteogenic efficiency.

Conclusion: The use of adipose-derived stem cell exosomes to encapsulate NPP-WSM can increase the utilization of WSM, promote the proliferation of MC3T3-E1, and enhance the osteogenic differentiation ability.

Estimates of the added benefit from COVID-19 vaccine booster doses can inform seasonal vaccine recommendations. We set out to estimate COVID-19 vaccine effectiveness (VE), avoiding common sources of bias. We chose a modified screening method, using only vaccinated cases of symptomatic COVID-19 recorded in the mandatory infectious disease reporting system, with data from a vaccination registry. Effect estimates were obtained by Bayesian logistic regression, comparing outcomes within dose strata between immunized (15-21d after vaccination) and not yet immunized (up to 7d). VE estimates were calculated recursively and relative VE estimates were obtained to quantify the added benefit of booster doses. We found VE for clinical illness to be around 90% during the predominance of the SARS-CoV-2 Alpha variant. During the Delta period, VE was distinctly lower, but did not decrease much further. The first booster dose added substantial protection during the Delta period, but that benefit became marginal during the Omicron period in the 18+. The effect of second booster doses, which became widespread only during the Omicron period, was modest. Using a novel, vaccinated-only study design we found that two doses of a COVID-19 vaccine offered substantial protection from symptomatic COVID-19, even during the Omicron period. One booster dose was highly effective during the Delta period, but the effect became modest during the Omicron period, when second booster doses offered, but a marginal benefit.

Cisplatin-based concurrent chemoradiation (CRT) remains the standard treatment for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), yet recurrence rates remain high. Attempts to combine immune checkpoint inhibitors with CRT have not improved outcomes, underscoring the need to better understand CRT-driven immunologic dynamics. Here, we performed longitudinal, multidimensional profiling of peripheral immunity in patients with LA-HNSCC at baseline (BSL), one month (CRT-1M), and three months (CRT-3M) after platinum-based CRT. CRT induced a transient reduction in tumor-reactive Th1 responses at CRT-1M, followed by marked expansion by CRT-3M. Consistently, genes involved in T-cell activation, polarization, and exhaustion exhibited a biphasic pattern with delayed upregulation at CRT-3M. Transcriptomic analyses of blood lymphocytes revealed an early shift from B-cell- to T-cell-mediated pathways over time during CRT. Integrated analyses including immunosuppressive cells and soluble mediators showed that the early decline in tumor-reactive T cells coincided with increased immunosuppressive cells, T-cell exhaustion, and elevated protumoral cytokines such as IL-8, IL-1β, and IL-10. In contrast, robust expansion of tumor-reactive T cells dominated the peripheral immune landscape at CRT-3M. Together, these data reveal the dynamic remodeling of peripheral immunity following platinum-based CRT and identify a delayed peripheral immune activation phase that may represent an optimal window for combining CRT with immune checkpoint blockade.

This study examines competition models based on the Lotka-Volterra form that incorporate starvation-driven diffusions (SDD). Such dispersal assumes that species disperse in response to resource abundance or scarcity in a heterogeneous habitat. The primary objective of this study is to examine how SDD, in combination with diverse interspecific interactions, affects species' fitness and coexistence states. To this end, the study introduces a refined classification for competing interactions based on a novel metric that quantifies the variability of resource heterogeneity across the environment. This approach contrasts with traditional models that assume uniform diffusion within homogeneous environments. This study investigates the local stability of two semitrivial steady states and establishes the existence and uniqueness of positive steady states by eigenvalue analysis and monotone dynamical systems theory. Through this analytical exploration, the study reveals that the interplay between species' dispersal strategies and the varying intensities of interspecific competition significantly impacts ecological outcomes.

Background: Oral food challenges are indicated when food allergies cannot be confirmed by clinical history or investigations, such as blood or skin-prick tests. However, few studies have examined adults' experiences of oral food challenges.

Methods: Semi-structured, individual interviews were conducted with 18 adults who had undergone an oral food challenge at a UK hospital.

Results: Three main themes were identified using thematic analysis, describing experiences before, during, and after testing: "A limited and scared life," "facing fear and uncertainty in a safe environment," and "living with revised boundaries." Prior to the test, participants described a life characterized by fear of reactions, hypervigilance, planning and restrictive diets, limiting social participation. During testing, participants experienced an emotional rollercoaster, confronting something previously avoided, which could potentially cause a severe reaction. After testing, participants reported reduced fear and uncertainty following clarification of their allergies, leading to greater freedom, and for those who tested negative, a return to viewing food as a source of pleasure, rather than fear.

Conclusions: Oral food challenges reduce fear and uncertainty surrounding allergies, providing clarity about which foods trigger reactions. Greater availability of oral food challenges would enable adults with suspected allergies to live less restricted and more enjoyable lives.

This work examines the dynamics of a discrete-time plankton interaction model, in which phytoplankton generate toxins and are vulnerable to external contamination. The model includes a Holling Type-II predation response and uses a piecewise constant argument approach to break it up into smaller pieces. This keeps the ecological realism of the continuous system while making it possible to study complex discrete-time behaviors. Our focus is on the formation of Neimark-Sacker bifurcation, a phenomena associated with the initiation of quasi-periodic oscillations in population densities. We show how toxin buildup and outside contamination can make plankton populations unstable, which could cause blooms to happen in an irregular way, using stability analysis and numerical simulations. The results show how useful discrete-time models are for capturing rapid changes in ecosystems, such damaging algal blooms. They also give ideas for managing ecosystems and reducing blooms.

In May 2022, a global outbreak of mpox (formerly known as monkeypox) was declared an international public health emergency. During this time, healthcare workers scrambled to respond to the outbreak amidst a lack of resources, knowledge gaps and pressures related to COVID-19. This period posed a risk of heightened moral distress, defined as distress arising from a situation in which a healthcare worker knows the right thing to do but is externally constrained from doing so. An international survey of healthcare workers was developed to understand their experiences of responding to mpox, including open-text questions regarding moral distress. Drawing on thematic analysis of these open text responses, this paper conceptualises the forms of distress experienced by health workers as 'outbreak distress'-an emotional and psychological response to the synergistic effects that arise from stressed systems, uncertainty and stigma that characterise many, and especially new, infectious disease outbreaks. In the context of pandemic preparedness, outbreak distress represents a novel concept for understanding additional pressures on healthcare systems in future unknown and re-emerging outbreaks.

Introduction: Evidence for mentorship largely focuses on traditional faculty-resident mentorship, with limited assessment of fellows as near-peer mentors. Our intervention develops and assesses a resident-fellow mentorship initiative.

Methods: We conducted a sequential, adaptive multi-method design program evaluation. First, to evaluate trainee attitudes and beliefs around fellows as residents' mentors we conducted annual surveys. Subsequently, interviews were used to iteratively understand how fellow-resident mentorship affected trainees' career development experiences in pursuit of fellowships.Our mentorship program at an academic pediatric hospital matched residents with fellows from 2020-2023 based on career subspecialty interests. Participants completed pre-intervention and post-participation surveys assessing experiences with prior mentorship, attitudes towards mentorship, and confidence in fellows as mentors. Subsequently in 2023, participants were recruited for qualitative, structured interviews to gain deeper understanding of experiences and recognize opportunities for program expansion and improvement.

Results: Seventy-two residents were paired with 53 fellows in dyads and triads of mentorship during the study period. Survey data revealed: 1) Less than half of residents (49%) and fellows (29%) previously had fellow mentorship; 2) Post-participation, 29% of residents and 21% of fellows completed surveys, and all accepted that fellows are capable mentors; 3) Lower satisfaction ratings on surveyed experience coincided with fewer meetings or mismatched specialty of interest.Subsequent interviews with 9 residents (post-match) and 9 fellows revealed: 1) The greatest benefit was strengthening residents' applications and insight into subspecialties; 2) Fellows were perceived as near-peers with deeper understanding and ease in communicating; 3) Barriers of time constraints and mismatch between specialties were underscored; 4) Fellows noted benefits of reflection opportunity and mentorship skill building.

Discussion: Implementation of a near-peer mentorship program for trainees interested in subspecialty careers provided an added layer of support in this single-center Pediatric training program. Fellows may be an underutilized resource for near-peer mentorship of trainees.

Objective: Clear-cell renal cell carcinoma (ccRCC) is an immune-desert tumor. This study investigates the role of ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) as a potential therapeutic target and immune-checkpoint enzyme in ccRCC.

Methods: ENPP3 expression and its link to hypoxia and prognosis were analyzed in ccRCC. Functional roles were tested using gain/loss-of-function studies in vitro and in xenograft models, followed by therapeutic anti-ENPP3 antibody administration, alone or with anti-PD-L1. Mechanisms were explored via promoter analysis, cGAMP measurement, flow cytometry, cytokine profiling, and in vivo neutralization with STING- or interferon-α/β receptor-1 (IFNAR1) blocking antibodies.

Results: ENPP3 is hypoxia-inducible via HIF-1α, upregulated in ccRCC, and predicts poor prognosis. ENPP3 overexpression accelerated tumor growth, while its knockdown or antibody blockade inhibited progression and synergized with anti-PD-L1. Mechanistically, ENPP3 hydrolyzes extracellular cGAMP. Its depletion elevated extracellular cGAMP, expanded anti-tumor immune cells (M1 macrophages, cDC1s, and cytotoxic T cells), reduced Tregs, and induced a STING- and IFNAR1-dependent type I interferon signature in macrophages. The anti-tumor efficacy of ENPP3 blockade was abrogated by IFNAR1 inhibition.

Conclusion: ENPP3 is a hypoxia-driven, cGAMP-targeting innate immune checkpoint in ccRCC. Its inhibition reactivates STING-dependent anti-tumor immunity, providing a strong preclinical rationale for targeting ENPP3 therapeutically.

Women's autonomy in fertility decision-making is essential for improved health and social outcomes. Guided by the social-ecological model, this investigation explores multilevel influences on the fertility autonomy of women with an unmet need for family planning in rural Uganda. We conducted four focus groups with men and women (n = 26), and 15 key informant interviews with community leaders and individuals involved in the provision of family planning. The data were analyzed thematically. The results highlight how community-level norms reinforce gender inequalities in decision-making and underpin beliefs to not limit men's number of children. Religious norms and polygamy practices were shown to influence attitudes towards family size and family planning, as well as shape relationship dynamics related to fertility. Concerns about poverty were identified as a driver of shifting preferences and increasing acceptance of family planning. Results showcase how health system weaknesses limit women's access to family planning services, contribute to mistrust of health systems and drive misinformation about contraceptives, especially among men. This study underscores the need for multifaceted gender transformative interventions to increase women's fertility autonomy. This study also highlights health system strengthening, religious leader endorsement and male engagement as approaches to increase women's autonomous use of family planning.